Discuss the principles of radioimmunotherapy.

Assignment Brief

What are the potential advantages and limitations of this approach for

1. haematological malignancies
2. solid tumours

word limit: 1,500

This is the essay title of an MSc in Nuclear Medicine

Sample Answer

Principles of Radioimmunotherapy

Radioimmunotherapy (RIT) is a form of targeted cancer treatment that uses monoclonal antibodies (mAbs) to deliver radioactive isotopes directly to tumour cells. The method combines the specificity of immunotherapy with the cell-killing power of radiation. Here’s how it works:

1. Selection of Target Antigen
   A tumour-specific antigen, such as CD20 on B‑cells, is identified.

2. Monoclonal Antibody Binding
   A monoclonal antibody is designed to bind tightly and specifically to the antigen.

3. Radiolabelling
   The antibody is tagged with a radioactive isotope, commonly Yttrium-90 or Iodine-131.

4. Administration and Targeting
   The radiolabelled antibody is infused into the patient. It circulates and binds to cancer cells expressing the specific antigen.

5. Radiation-Driven Cell Death
   The radioactive isotope emits radiation that kills the cancer cell it’s attached to, and adjacent cells, through the “cross-fire” effect.

a) Hematological Malignancies

Advantages

1. High Target Specificity
   Diseases like non-Hodgkin lymphoma overexpress CD20, making them ideal for targeted therapy.

2. Effective in Small-Scale Disease
   Blood cancers often consist of small or diffuse cell clusters, which are accessible to antibodies circulating in the bloodstream.

3. Clinical Success
   Treatments like Ibritumomab tiuxetan (Zevalin®) and Tositumomab (Bexxar®) have been approved and shown high response rates, especially in relapsed or refractory lymphoma.

4. Cross-Fire Effects
   Radiation from one radiolabelled cell can kill neighbouring cancer cells even without direct antibody binding.

5. Synergy with Other Therapies
   RIT is often used with chemotherapy or as a consolidation therapy to deepen remissions.

Limitations

1. Bone Marrow Toxicity
   Radioisotopes tend to accumulate in the marrow, which can cause neutropenia and thrombocytopenia.

2. Immunogenic reactions
   Some patients may develop human anti-mouse antibodies (HAMA) against murine mAbs, reducing effectiveness.

3. Dosimetry Challenges
   Determining a precise radiation dose requires individual scans and blood tests, making treatment complex.

4. Limited by Disease Burden
   RIT works best in smaller, minimal residual disease; bulky tumours tend to clear less efficiently.

b) Solid Tumours

Potential Advantages

1. Selective Targeting
   Monoclonal antibodies can be designed to target tumour-specific antigens, e.g., HER2 in breast cancer or CEA in colon cancer.

2. Cross-Fire Effect Is Beneficial
   Radiation does not require every cell to be directly bound by antibody, helping to reach cells within a solid tumour mass.

3. Combining with Other Modalities
   RIT can be used with chemotherapy, surgery, or external beam radiation to treat micrometastases or residual disease.

4. Minimal Systemic Effects
   Compared to conventional chemotherapy, RIT tends to spare healthy tissue due to targeted radiation delivery.

Limitations

1. Delivery Barriers
   Solid tumours have poor blood flow and elevated internal pressure, limiting antibody penetration.

2. Antigen Heterogeneity
   Tumours often express variable levels of target antigens, leading to incomplete targeting and cross-resistance.

3. Dose Limitations and Toxicity
   Higher doses may damage nearby healthy tissues and increase systemic radiation exposure.

4. Manufacturing and Cost
   Producing radiolabelled antibodies under strict safety regulations is expensive and complex, making it hard to scale.

5. Immunogenicity and Resistance
   Even humanised mAbs may provoke immune responses or activate tumour resistance mechanisms.

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